Role of Chemoradiation in Resectable Pancreatic Cancer

John L. Marshall, MD: Who is a patient for whom you would recommend gemcitabine/capecitabine in the adjuvant setting tomorrow? Toni?

Tanios S. Bekaii-Saab, MD: Assuming that postoperative therapy is our standard, which it’s not for most patients, I would go with Eileen’s thoughts about how this is going to be limited to the patients that have a hard time recovering from surgery—patients who are perhaps older—although that’s not a necessarily easy regimen to give. You really have to cut down significantly on the dose of the capecitabine and oftentimes find yourself going to every other week in some patients. So, it’s not necessarily a trip in the park itself. It’s tough, but nonetheless, it’s a less intense treatment. Now, we’re missing 1 thing, and we’ll hear soon, I hope, about the results of APACT study with gemcitabine/nab-paclitaxel versus gemcitabine. Another randomized phase III study, I think, will report later this year, and that certainly would add yet another option.

John L. Marshall, MD: But if we’re really data driven, this is surgery first, followed by FOLFIRINOX with the best number we’ve ever seen. Is this fair? Is that right?

Eileen M. O’Reilly, MD: Absolutely.

John L. Marshall, MD: Why are you holding on to chemotherapy first?

Tanios S. Bekaii-Saab, MD: I think, again, you have to think about how you select your patients.

John L. Marshall, MD: But is it going to be better? You’re just assuming it’s going to be better frontline.

Tanios S. Bekaii-Saab, MD: The whole concept of moving this total neoadjuvant therapy in rectal cancer was based on the fact that we still miss 10%, 15% of the patients who never receive treatment, that we know—and the same with esophagus cancer—when we put all this together, that chemotherapy, radiation plus surgery improves outcome; at least chemotherapy plus surgery, maybe radiation. So, exposing the maximum number of patients and selecting the best way for our patients to get to surgery is, obviously, to do this neoadjuvant approach. I do believe that these are compelling, and, in fact, I see them as supportive. We have another study—Dr. O’Reilly is going to be talking about it—that suggests that perhaps neoadjuvant approach makes more sense anyway.

John L. Marshall, MD: Let’s go to that—so, tell us about this clinical trial.

Eileen M. O’Reilly, MD: New data for adjuvant endorsement and, I think, new data supporting this strategy of neoadjuvant strategy. It’s a Dutch trial; 250 patients with potentially resectable or borderline resectable pancreas cancer were randomized to either upfront surgery or upfront neoadjuvant therapy. And that was a cycle of gemcitabine followed by 15 fractions of radiation and gemcitabine and surgery, and everybody got postoperative adjuvant therapy. The numbers are very different than what we see in the FOLFIRINOX group, and we have to emphasize the selection in the latter study. But the study was positive in favor of neoadjuvant therapy, and it continues. We’re getting more and more data. We have National Cancer Database (NCDB) analysis; we have multiple large cohorts now, sort of highlighting this theme of how getting more treatment into more patients early improves outcome. And, yes, it’s selection, but ultimately, that’s what we want to do, right? We want to select best who’s going to benefit from an operation because that’s the most significant intervention for most patients, in terms of their tolerability and recovery, etc.

John L. Marshall, MD: Is the next study 3 months of FOLFIRINOX, then surgery versus surgery followed by FOLFIRINOX?

Eileen M. O’Reilly, MD: The Dutch are going to take this forward, and they’re going to adapt what we know with FOLFIRINOX, and they’re going to adapt what we know with their positive neoadjuvant study. That’s the next question that’s going to be asked. I don’t think that will necessarily apply to North America, in terms of how we approach our treatments.

John L. Marshall, MD: So, we’re just going to do it. We’re going to tweet it and do it.

Eileen M. O’Reilly, MD: I think we’re going to continue to embrace neoadjuvant, but we now have more data to support an upfront study.

Tanios S. Bekaii-Saab, MD: We do have the SWOG study to inform us somewhat, although it’s limited by the number of cycles that would be given prior to surgery with FOLFIRINOX versus gemcitabine/nab-paclitaxel. In the clearly resectable patients, this will inform us a little bit more about at least the American practice. But the 2 backbones—at least 1 of them now is showing great data in the adjuvant setting and waiting on the other 1, and we’ll see what it is at the end of the day. But we’re getting smarter about how we do it.

John L. Marshall, MD: If there’s a gemcitabine-based therapy with positive 5-FU–based, should we be doing both in the adjuvant setting and try to keep pushing that care bar up?

Tanios S. Bekaii-Saab, MD: This is very interesting, because we’ve done a study in esophagus cancer similarly through Alliance, where you predict by PET scan who are those patients who need to switch the backbone. And we’re doing a similar approach, as I alluded to, with the PET-MRI. We’re trying to look at switching patients who do not have a maximal response from the treatment—typically, FOLFIRINOX; occasionally, gemcitabine/nab-paclitaxel. We’re doing the switch if there’s no maximal, biochemical, and metabolic response, so there’s certainly benefit. And we do see in our cohorts that there is a benefit to that switch. But, again, it’s a single-institution study. We need to certainly validate it beyond that point. Again, it could be just selecting better patients for the surgery, but, as Eileen alluded to, that’s really what we need. We need to make sure that the patient who goes to surgery really has the best chance to benefit from that surgery.

Kabir Mody, MD: But any of us, we all see a lot of pancreatic cancer. We all know through the medicine, instinctively, that there are patients who do better with a 5-FU–based regimen and some who do better with a gemcitabine-based one.

John L. Marshall, MD: We can’t predict it.

Kabir Mody, MD: Exactly right. We’re not there yet.

Tanios S. Bekaii-Saab, MD: I like that crystal ball.

John L. Marshall, MD: We need that molecular marker to tell us.

Tanios S. Bekaii-Saab, MD: That would save so much money in drug development.

Eileen M. O’Reilly, MD: There are a lot of strategies trying to do this—trying to select which approach we should take, looking at pharmacogenomics, looking at CTC (circulating tumor cells) analysis, looking at the tumor and seeing if you can predict, based on this basal or classical subtype, who are the group of people that could potentially benefit.

John L. Marshall, MD: Dr. Mody, help me on this. So, we have surgery first and node-positive, adjuvant FOLFIRINOX, margin negative. Does that patient need some radiation?

Kabir Mody, MD: No. I think that there’s no convincing evidence that radiation benefits patients in terms of overall survival. But I think there is some value to risk-stratifying the radiation in patients—so, patients with positive margins, patients with nodes, patients who are more at risk of local recurrence of their disease.

John L. Marshall, MD: Is anybody radiating that patient?

Tanios S. Bekaii-Saab, MD: No.

John L. Marshall, MD: Maybe?

Eileen M. O’Reilly, MD: We’ll have data. The RTOG 0848 study, the long-standing study, is now closed to new patients, which is great, and we’ll hopefully be able to answer if there’s a subset of patients who do benefit from the routine inclusion of radiation following their standard adjuvant treatment.

John L. Marshall, MD: I think the radiation doctors have done a good job here of backing off in this space; although there are many who, if you send them, they’ll radiate them.

Tanios S. Bekaii-Saab, MD: They’re still not very happy about it, but I think that until these data, there’s really no convincing evidence of that; my rule of thumb is, the R0 resection patients may actually benefit more from radiation than the R1.

John L. Marshall, MD: Backward of what our instincts would say?

Tanios S. Bekaii-Saab, MD: It has to. The R1 is a surrogate for metastatic disease and local control.

John L. Marshall, MD: That’s the one where we send and they treat.

Tanios S. Bekaii-Saab, MD: So, we have to be careful.

Eileen M. O’Reilly, MD: Yes, I actually think we’re going to be using more radiation as our systemic therapies get better, because this is going to become a bigger problem—so, rather than the other way around.

George P. Kim, MD: We talk about patient selection, and I think we have to follow what the French have done. This is all post operative. We can debate preoperative, post operative. Right now, it’s all post operative, and also the CA19-9—that’s a key. You want to talk about patient selection; less than 180, very important. So, that’s going to help us.

John L. Marshall, MD: What do I do with the patient who’s got a CA19-9; am I not going to give them FOLFIRINOX?

George P. Kim, MD: You’re going to treat them anyway. Look at 3 years of follow-up; median survival is 54 months. That’s a long time.

John L. Marshall, MD: For us, yes.

George P. Kim, MD: That’s big in pancreas cancer. That’s very close to the 5-year cure rate for the median. So, I think that’s where we are; we’ve said it already. We need to dose modify, get rid of the bolus—apparently that is what they did—and bring the irinotecan down to 150mg/m². So, I think we’re going to see that more and more in the real world, in the community, and I think that’s where we are right now. These other issues about imaging and preoperative, postoperative—we have to resolve that.

Tanios S. Bekaii-Saab, MD: We have compelling data preoperative already, and I think the numbers that you see in this study are not very different from the numbers we see from large databases in terms of applying neoadjuvant approaches; they’re about the same. So, the goal: If we’re seeing numbers that look very similar, whether we give before or after, and you select your patients well, if you give before, and you expose more patients that are likely to benefit—I think the case can be made. I understand the value of studies, and we should continue to look at studies. I find it hard to have 20% of my patients miss on adjuvant therapy; I’d like to give it up front.

Transcript Edited for Clarity

SELECTEDLANGUAGE

Transcript:

John L. Marshall, MD: Who is a patient for whom you would recommend gemcitabine/capecitabine in the adjuvant setting tomorrow? Toni?

Tanios S. Bekaii-Saab, MD: Assuming that postoperative therapy is our standard, which it’s not for most patients, I would go with Eileen’s thoughts about how this is going to be limited to the patients that have a hard time recovering from surgery—patients who are perhaps older—although that’s not a necessarily easy regimen to give. You really have to cut down significantly on the dose of the capecitabine and oftentimes find yourself going to every other week in some patients. So, it’s not necessarily a trip in the park itself. It’s tough, but nonetheless, it’s a less intense treatment. Now, we’re missing 1 thing, and we’ll hear soon, I hope, about the results of APACT study with gemcitabine/nab-paclitaxel versus gemcitabine. Another randomized phase III study, I think, will report later this year, and that certainly would add yet another option.

John L. Marshall, MD: But if we’re really data driven, this is surgery first, followed by FOLFIRINOX with the best number we’ve ever seen. Is this fair? Is that right?

Eileen M. O’Reilly, MD: Absolutely.

John L. Marshall, MD: Why are you holding on to chemotherapy first?

Tanios S. Bekaii-Saab, MD: I think, again, you have to think about how you select your patients.

John L. Marshall, MD: But is it going to be better? You’re just assuming it’s going to be better frontline.

Tanios S. Bekaii-Saab, MD: The whole concept of moving this total neoadjuvant therapy in rectal cancer was based on the fact that we still miss 10%, 15% of the patients who never receive treatment, that we know—and the same with esophagus cancer—when we put all this together, that chemotherapy, radiation plus surgery improves outcome; at least chemotherapy plus surgery, maybe radiation. So, exposing the maximum number of patients and selecting the best way for our patients to get to surgery is, obviously, to do this neoadjuvant approach. I do believe that these are compelling, and, in fact, I see them as supportive. We have another study—Dr. O’Reilly is going to be talking about it—that suggests that perhaps neoadjuvant approach makes more sense anyway.

John L. Marshall, MD: Let’s go to that—so, tell us about this clinical trial.

Eileen M. O’Reilly, MD: New data for adjuvant endorsement and, I think, new data supporting this strategy of neoadjuvant strategy. It’s a Dutch trial; 250 patients with potentially resectable or borderline resectable pancreas cancer were randomized to either upfront surgery or upfront neoadjuvant therapy. And that was a cycle of gemcitabine followed by 15 fractions of radiation and gemcitabine and surgery, and everybody got postoperative adjuvant therapy. The numbers are very different than what we see in the FOLFIRINOX group, and we have to emphasize the selection in the latter study. But the study was positive in favor of neoadjuvant therapy, and it continues. We’re getting more and more data. We have National Cancer Database (NCDB) analysis; we have multiple large cohorts now, sort of highlighting this theme of how getting more treatment into more patients early improves outcome. And, yes, it’s selection, but ultimately, that’s what we want to do, right? We want to select best who’s going to benefit from an operation because that’s the most significant intervention for most patients, in terms of their tolerability and recovery, etc.

John L. Marshall, MD: Is the next study 3 months of FOLFIRINOX, then surgery versus surgery followed by FOLFIRINOX?

Eileen M. O’Reilly, MD: The Dutch are going to take this forward, and they’re going to adapt what we know with FOLFIRINOX, and they’re going to adapt what we know with their positive neoadjuvant study. That’s the next question that’s going to be asked. I don’t think that will necessarily apply to North America, in terms of how we approach our treatments.

John L. Marshall, MD: So, we’re just going to do it. We’re going to tweet it and do it.

Eileen M. O’Reilly, MD: I think we’re going to continue to embrace neoadjuvant, but we now have more data to support an upfront study.

Tanios S. Bekaii-Saab, MD: We do have the SWOG study to inform us somewhat, although it’s limited by the number of cycles that would be given prior to surgery with FOLFIRINOX versus gemcitabine/nab-paclitaxel. In the clearly resectable patients, this will inform us a little bit more about at least the American practice. But the 2 backbones—at least 1 of them now is showing great data in the adjuvant setting and waiting on the other 1, and we’ll see what it is at the end of the day. But we’re getting smarter about how we do it.

John L. Marshall, MD: If there’s a gemcitabine-based therapy with positive 5-FU–based, should we be doing both in the adjuvant setting and try to keep pushing that care bar up?

Tanios S. Bekaii-Saab, MD: This is very interesting, because we’ve done a study in esophagus cancer similarly through Alliance, where you predict by PET scan who are those patients who need to switch the backbone. And we’re doing a similar approach, as I alluded to, with the PET-MRI. We’re trying to look at switching patients who do not have a maximal response from the treatment—typically, FOLFIRINOX; occasionally, gemcitabine/nab-paclitaxel. We’re doing the switch if there’s no maximal, biochemical, and metabolic response, so there’s certainly benefit. And we do see in our cohorts that there is a benefit to that switch. But, again, it’s a single-institution study. We need to certainly validate it beyond that point. Again, it could be just selecting better patients for the surgery, but, as Eileen alluded to, that’s really what we need. We need to make sure that the patient who goes to surgery really has the best chance to benefit from that surgery.

Kabir Mody, MD: But any of us, we all see a lot of pancreatic cancer. We all know through the medicine, instinctively, that there are patients who do better with a 5-FU–based regimen and some who do better with a gemcitabine-based one.

John L. Marshall, MD: We can’t predict it.

Kabir Mody, MD: Exactly right. We’re not there yet.

Tanios S. Bekaii-Saab, MD: I like that crystal ball.

John L. Marshall, MD: We need that molecular marker to tell us.

Tanios S. Bekaii-Saab, MD: That would save so much money in drug development.

Eileen M. O’Reilly, MD: There are a lot of strategies trying to do this—trying to select which approach we should take, looking at pharmacogenomics, looking at CTC (circulating tumor cells) analysis, looking at the tumor and seeing if you can predict, based on this basal or classical subtype, who are the group of people that could potentially benefit.

John L. Marshall, MD: Dr. Mody, help me on this. So, we have surgery first and node-positive, adjuvant FOLFIRINOX, margin negative. Does that patient need some radiation?

Kabir Mody, MD: No. I think that there’s no convincing evidence that radiation benefits patients in terms of overall survival. But I think there is some value to risk-stratifying the radiation in patients—so, patients with positive margins, patients with nodes, patients who are more at risk of local recurrence of their disease.

John L. Marshall, MD: Is anybody radiating that patient?

Tanios S. Bekaii-Saab, MD: No.

John L. Marshall, MD: Maybe?

Eileen M. O’Reilly, MD: We’ll have data. The RTOG 0848 study, the long-standing study, is now closed to new patients, which is great, and we’ll hopefully be able to answer if there’s a subset of patients who do benefit from the routine inclusion of radiation following their standard adjuvant treatment.

John L. Marshall, MD: I think the radiation doctors have done a good job here of backing off in this space; although there are many who, if you send them, they’ll radiate them.

Tanios S. Bekaii-Saab, MD: They’re still not very happy about it, but I think that until these data, there’s really no convincing evidence of that; my rule of thumb is, the R0 resection patients may actually benefit more from radiation than the R1.

John L. Marshall, MD: Backward of what our instincts would say?

Tanios S. Bekaii-Saab, MD: It has to. The R1 is a surrogate for metastatic disease and local control.

John L. Marshall, MD: That’s the one where we send and they treat.

Tanios S. Bekaii-Saab, MD: So, we have to be careful.

Eileen M. O’Reilly, MD: Yes, I actually think we’re going to be using more radiation as our systemic therapies get better, because this is going to become a bigger problem—so, rather than the other way around.

George P. Kim, MD: We talk about patient selection, and I think we have to follow what the French have done. This is all post operative. We can debate preoperative, post operative. Right now, it’s all post operative, and also the CA19-9—that’s a key. You want to talk about patient selection; less than 180, very important. So, that’s going to help us.

John L. Marshall, MD: What do I do with the patient who’s got a CA19-9; am I not going to give them FOLFIRINOX?

George P. Kim, MD: You’re going to treat them anyway. Look at 3 years of follow-up; median survival is 54 months. That’s a long time.

John L. Marshall, MD: For us, yes.

George P. Kim, MD: That’s big in pancreas cancer. That’s very close to the 5-year cure rate for the median. So, I think that’s where we are; we’ve said it already. We need to dose modify, get rid of the bolus—apparently that is what they did—and bring the irinotecan down to 150mg/m². So, I think we’re going to see that more and more in the real world, in the community, and I think that’s where we are right now. These other issues about imaging and preoperative, postoperative—we have to resolve that.

Tanios S. Bekaii-Saab, MD: We have compelling data preoperative already, and I think the numbers that you see in this study are not very different from the numbers we see from large databases in terms of applying neoadjuvant approaches; they’re about the same. So, the goal: If we’re seeing numbers that look very similar, whether we give before or after, and you select your patients well, if you give before, and you expose more patients that are likely to benefit—I think the case can be made. I understand the value of studies, and we should continue to look at studies. I find it hard to have 20% of my patients miss on adjuvant therapy; I’d like to give it up front.